Whole-Exome Sequencing Explores Host Genetic Susceptibility of COVID-19 Severity in Unvaccinated Vietnamese Patients Infected with the Delta Variant: A Hypothesis-Generating Study.

Background/

Objectives

Host genetic variation contributes to the heterogeneous clinical outcomes of coronavirus disease 2019 (COVID-19), yet evidence from Southeast Asian populations remains limited.

Methods

We investigated host genetic factors associated with COVID-19 severity in Vietnamese patients infected with the SARS-CoV-2 Delta variant using whole-exome sequencing. A total of 48 unvaccinated patients were enrolled. During sample-level quality control, one sample was excluded because the genetically inferred sex was discordant with the information recorded in the clinical medical record, leaving 47 samples (23 severe/critical and 24 mild/asymptomatic) for downstream genetic analyses. Gene-based association analysis was performed using MAGMA, followed by functional enrichment and interaction network analyses with Metascape and GeneMANIA.

Results

Population structure analysis showed that the study participants clustered closely with the East Asian (EAS) reference population. No individual variant reached the prespecified multiple-testing-adjusted threshold, and no gene-level association survived Benjamini-Hochberg correction. Using a nominal MAGMA gene-based p < 0.01 threshold solely for exploratory prioritization, 44 genes were selected for downstream functional analyses. Functional enrichment highlighted RNA processing and mRNA maturation, together with mitochondrial, metabolic, immune-regulatory, and cellular homeostasis pathways. Network topology analysis further identified several highly connected genes, including CPSF4, MRPS34, ATP5MF, BUD31, SNRPD3, and HDAC1.

Conclusions

These hypothesis-generating findings are consistent with a potentially polygenic contribution to severe COVID-19 and provide an exploratory systems-level framework for understanding host genetic susceptibility in the Vietnamese population, while identifying biologically plausible candidate genes and pathways for future validation.